Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the invention relates to compounds, compositions, and methods for the treatment of human immunodeficiency virus (HIV) infection. More particularly, the invention relates to novel inhibitors of HIV, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection. The invention also relates to methods for making the compounds hereinafter described.
• HIV human immunodeficiency virus
• AIDS Acquired immunodeficiency syndrome
• HIV-infected individuals consists of a combination of approved anti-retroviral agents. Close to four dozen drugs are currently approved for HIV infection, either as single agents, fixed dose combinations or single tablet regimens; the latter two containing 2-4 approved agents. These agents belong to a number of different classes, targeting either a viral enzyme or the function of a viral protein during the virus replication cycle.
• agents are classified as either nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), or entry inhibitors (one, maraviroc, targets the host CCR5 protein, while the other, enfuvirtide, is a peptide that targets the gp41 region of the viral gp160 protein).
• a pharmacokinetic enhancer cobicistat or ritonavir
• ARVs antiretroviral agents
• the present invention discloses a compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein:
• the present invention discloses a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
• the present invention discloses a method of treating HIV infection in a human comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient.
• the present invention discloses a compound of Formula I or pharmaceutically acceptable salt thereof for use in therapy.
• the present invention discloses a compound of Formula I or pharmaceutically acceptable salt thereof for use in treating HIV infection in a human.
• the present invention discloses the use of a compound of Formula I or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of HIV infection in a human.
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein W is the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein W is the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein W is one of the following: wherein R 4 is methyl optionally substituted with 1-3 fluorines.
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein R 1 is Cl; R 2 is methyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl; and R 3 is methyl or cyclopropyl.
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein X 3 is H.
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein X 1 is F, X 2 is F, and X 3 is H.
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein if X 3 is H then at least one of X 1 and X 2 is other than F.
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein G 1 is one of the following:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein the stereochemistry is as depicted below:
• the present invention discloses compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein the stereochemistry is as depicted below:
• the present invention discloses compounds and salts, selected from the group consisting of: and pharmaceutically acceptable salts thereof.
• the present invention discloses compounds and salts, selected from the group consisting of: and pharmaceutically acceptable salts thereof.
• the present invention discloses compounds and salts, selected from the group consisting of: and pharmaceutically acceptable salts thereof.
• the present invention discloses the compound: and pharmaceutically acceptable salts thereof.
• the salts of the invention are pharmaceutically acceptable. Such salts may be acid addition salts or base addition salts.
• suitable pharmaceutically acceptable salts see, for example, Berge et al, J. Pharm, Sci., 66, 1-19, 1977 .
• Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (
• Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (/V-benzylphenethylamine), benzathine ( N , N'- dibenzylethylenediamine), bis -(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1- p chlorobenzyl-2-pyrrolildine-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine ( N -methylglucamine), piperazine, piper
• compositions of this invention further comprise a pharmaceutically acceptable excipient.
• preferred routes of administration are oral and by injection to deliver subcutaneously or intramuscularly. Therefore, preferred pharmaceutical compositions include compositions suitable for oral administration (for example tablets) and compositions suitable for subcutaneous or intramuscular injection.
• Pre-exposure prophylaxis is when people at risk for HIV infection take daily medicine to lower their chances of getting HIV infection. PrEP has been shown to be effective in reducing the risk of infection.
• HIV HIV or “Human Immunodeficiency Virus” refers to HIV-1 and/or to HIV-2.
• Combination therapies according to the present invention thus comprise the administration of at least one compound or salt of the invention, and the administration of at least one other agent which may be useful in the treatment of HIV infection.
• a compound or salt of the present invention, and the other agent may be formulated and administered together in a single pharmaceutical composition or may be formulated and administered separately. When formulated and administered separately, administration may occur simultaneously or sequentially in any order.
• Suitable other agents include, for example, abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, the antibody N6LS, GSK3739937/VH3739937 and GSK4000422/VH4000422, indinavir, lamivudine, lopinavir, maraviroc, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, saquinavir, slatravir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoprox
• Preferred agents include, for example, bictegravir, cabotegravir, dolutegravir, fostemsavir, islatravir, and lamivudine.
• Particularly preferred agents include, for example, bictegravir, cabotegravir, dolutegravir, fostemsavir, and lamivudine.
• the column was eluted with a gradient. The start %B and ending %B were optimized for each compound. Generally, the gradient ran for 6 minutes followed by a 2 minute hold at 98% B.
• the reaction mixture was filtered, and the filter cake was extracted with EtOAc (1000 mL). The filtrate was washed with saturated aq. Na 2 S 2 O 3 (2 ⁇ 500 mL); saturated aq. FeSO 4 (300 mL); and then brine (500 mL).
• the organic layer was dried over anhydrous Na 2 SO 4 ,; filtered and concentrated under reduced pressure to obtain the crude title compound (150 g).
• the resulting solution was concentrated under reduced pressure and the resulting solids were dissolved in EtOAc, then twice washed with aq. citric acid (1M) followed by water followed by brine. The organic solution was dried over Na 2 SO 4 ; filtered; then concentrated in vacuo to afford the separated enantiomer in 80-90% recovery.
• Step-2a To a solution of DMSO (5.9 L, 5.0 V)) in a round-bottom flask was added 2,6-dichloro-3-nitrobenzaldehyde (1.17 kg, 5.31 mol, 1.0 equiv.) at room temperature. After being stirred for 30 min at room temperature, hydroxylamine hydrochloride (0.63 kg, 9.04 mol, 1.70 equiv.) was added and the reaction mass was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched by the addition of ice-cold water (18.0 L, 15.0 V) added at a rate sufficient to maintain the temperature below 30 °C (Observation: Solids formed upon water addition).
• the reaction mass was stirred at room temperature for 60-90 min.
• the solids were isolated by filtration; washed with water (2.5 L, 2.0 V); followed by washing with a mixture of acetone and hexanes (6.0 L, 1:1 ratio). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min.
• the wet solid was initially air dried and then finally dried in a hot air oven at 50-55 °C for 10-12 h (until moisture content was not more than 1.0 %) to get the dried target product, 2,6-dichloro-3-nitrobenzaldehyde oxime (1.22 kg, 92% yield) as an off-white solid.
• the crude product (which contains 10-20% of 2,6-dichloro-3-nitrobenzonitrile) was used directly in the next step without further purification.
• Step-2b To a stirred solution of the crude oxime (preparation described above, 1.13 kg, 4.80 mol, 1.0 equiv.) in DCM (9.04 L, 8.0 V) at 0-5 °C was added triethylamine ("TEA", 1.02 kg, 10.09 mol, 2.1 equiv.). After being stirred for 5 min, methanesulfonyl chloride (0.60 kg, 5.29 mol, 1.1 equiv.) was added (Observation: An exotherm is noted during the addition) slowly at 15 °C. Then the reaction mass was stirred at room temperature for 30-45 min.
• TOA triethylamine
• reaction mass was diluted with water (6.78 L, 6.0 V); the organic layer was separated; and the aqueous layer was extracted with DCM (3.4 L, 3.0 V). The combined organic layers were washed with brine (5.65 L, 5.0 V); dried over Na 2 SO 4 ; and concentrated under vacuum. The resulting crude solids were triturated with hexanes (4.50 L, 4.0 V) at room temperature.
• the solids were isolated via filtration and then were washed with water (2.25 L, 3.0 V).
• the wet solid was washed with a 1:1 ratio mixture of acetone (1.875 L, 2.5 V) and hexanes (1.875 L, 2.5 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min.
• the wet solid was finally dried in a hot air oven for 7-8 h at 50 °C (until moisture content reaches below 1.5%) to get the dried product, 4-chloro-7-nitro-1 H -indazol-3-amine (549.0 g, 75% yield) as a brick red-colored solid.
• reaction temperature was slowly raised to room temperature and stirring was continued an additional 2 h at the same temperature.
• reaction mass was quenched by the addition of ice-cold water (15.0 L, 30.0 V) and the resulting mixture was then stirred for 6-8 h at room temperature.
• the solids were isolated via filtration and were then washed with water (1.5 L, 3.0 V).
• the wet solid was washed with IPA (1.5 L, 3.0 V) followed by hexanes (1.0 L, 2.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min.
• Step 5 Preparation of N -(4-chloro-l-methyl-7-nitro-1 H -indazol-3-yl)methanesulfonamide
• Step 5a To a solution of 4-chloro-1-methyl-7-nitro-1 H- indazol-3-amine (625.0 g, 2.76 mol, 1.0 equiv.) in DCM (6.25 L, 10.0 V) at 0-5 °C. was added triethylamine (TEA) (837.0 g, 8.27 mol, 3.0 equiv.); followed by the addition of 4-dimethylaminopyridine (DMAP) (20.60 g, 0.165 mol, 0.06 equiv.).
• TEA triethylamine
• DMAP 4-dimethylaminopyridine
• reaction mass was stirred at the same temperature for 3 h.
• sample preparation for TLC analysis ⁇ 1.0 ml of sample acidified with aq. 2.0 N HCl to reach the pH: 2-3, extract it with ethyl acetate and analyze the organic layer by TLC
• the reaction mass was cooled to 0-5 °C and the pH was adjusted to 2-3 by the addition of aq. 2.0 N HCl (3.13 L, 5.0 V) while maintain the reaction temperature below 10 °C [Note: Precipitation occurred upon addition of HCl and increased with stirring].
• Step 6 Preparation of N -(4-chloro-1-methyl-7-nitro-1 H -indazol-3-yl)- N -(4-methoxybenzyl)methanesulfonamide
• the mixture was poured into ice cold water (19.05 L, 30.0 V) [Note: Slow quenching with vigorous stirring is preferred to avoid clumping as the product precipitates].
• the resulting solids were isolated via filtration and washed with water (1.90 L, 3.0 V); then the solids were washed with hexanes (1.27 L, 2.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min.
• the isolated solid was dissolved in Ethyl acetate (12.7 L, 20.0 V) and charcoal was added (63.5 g). The mixture was heated to 60-70 °C and then stirred for 30-45 min. at that temperature.
• Step 7 Preparation of N -(7-Amino-4-chloro-l-methyl-1 H -indazol-3-yl)- N -(4-methoxybenzyl)methanesulfonamide
• Step 1 Preparation of 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1 H -indazol-3-amine
• the solids were isolated via filtration and were then washed with water (540 mL, 3.0 V). The wet solid was washed with hexanes (0.9 L, 5.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 °C (until the moisture content was below 1.0%).
• the isolated material 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1 H -indazol-3-amine (160 g, 71% yield), was used in the next step without further purification.
• Step 2 Preparation of N -(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1 H -indazol-3-yl)methane sulfonamide
• Step 2a To a solution of 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1 H -indazol-3-amine (170.0 g, 0.96 mol, 1.0 equiv.) in DCM (1.7 L, 10.0 V) at 0-5 °C was added triethyl amine (264 mL, 2.88 mol, 3.0 equiv.), followed by 4-dimethylaminopyridine (3.4 g, 0.048 mol, 0.05 equiv.). The reaction mass was stirred for 5-10 min., then methanesulfonyl chloride (120 mL, 2.4 mol, 2.5 equiv.) was added slowly while maintaining the reaction mass below 10 °C.
• the reaction mixture was allowed to warm to room temperature and then was stirred for 1.5-2.0 h. After completion of the reaction (monitored by TLC), the mixture was diluted with water (1.7 L, 10.0 V) and then stirred at room temperature for 15 min. The organic layer was separated, and the aqueous layer was extracted with DCM (1.7 L, 10.0 V). The combined organic layers were washed with 10% brine solution (340 mL, 2.0 V), dried over Na 2 SO 4 and concentrated to afford the product as a crude solid.
• Step 2b To a stirred solution of N -(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1 H -indazol-3-yl)- N -(methylsulfonyl) methanesulfonamide (entirety of material prepared above) in ethanol (1.7 L, 10.0 V) at room temperature was added slowly aq. 5% NaOH solution (1.19 L, 7.0 V) [Note: Slow addition is preferred via dropping funnel]. The reaction mass was stirred at the same temperature for 3 h. After completion of the reaction [Sample preparation for TLC analysis: an aliquot of reaction solution ( ⁇ 1 mL) was acidified with aq.
• Step 3 Preparation of N -(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1 H -indazol-3-yl)- N -(4-methoxy benzyl)methanesulfonamide
• the mixture was poured into ice cold water (4.8 L, 60.0 V) [Note: Slow quenching with vigorous stirring is preferred to avoid clumping as the product precipitates].
• the resulting solids were isolated via filtration and washed with water (480 mL, 3.0 V); then the solids were washed with hexanes (320 mL, 2.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 1-2 h.
• the isolated solid was dissolved in ethyl acetate (1.6 L, 10.0 V) and charcoal was added (16.0 g). The mixture was heated to 60-70 °C and then stirred for 30-45 min. at that temperature.
• the mixture was filtered while hot (40-50 °C) through a pad of Celite and the Celite pad was then extracted with ethyl acetate (800 mL, 5.0 V).
• the combined filtrates were concentrated to dryness under reduced pressure at below 50 °C.
• ethyl acetate 160 mL, 1.0 V.
• the suspension was stirred for 30 min.
• the solids were isolated via filtration and then were washed with hexanes (320 mL, 2.0 V). Residual water was removed from the solids by maintaining vacuum filtration for 45-60 min.
• Step 4 Preparation of N -(7-amino-4-chloro-1-(2,2-difluoroethyl)-1 N -indazol-3-yl)- N -(4-methoxybenzyl)methanesulfonamide
• the reaction mixture was heated to 60 °C and then stirred for 2 h. After completion of the reaction (monitored by in-process TLC/HPLC), the mixture was cooled to room temperature and diluted with ethyl acetate (1.3 L, 10.0 V) and water (390 mL, 3.0 V). The mixture was stirred for 15 min. The mixture was filtered through a pad of Celite and the Celite pad was then extracted with ethyl acetate (650 mL, 5.0 V). The bi-phasic filtrate was partitioned, and the organic phase was reserved while the aqueous layer was extracted with ethyl acetate (650 mL, 5.0 V).
• Step 1 Preparation of N -(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1 H -indazol-3-yl)cyclopropanesulfonamide
• the reaction mixture was heated to 50 °C and then stirred at that temperature for 3 days. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and diluted with water (1.5 L, 10.0 V) and ethyl acetate (1.5 L, 10.0 V), then stirred at room temperature for 15 min. The organic layer was separated, and the aqueous layer was extracted with EtOAc (300 mL, 2.0 V). The combined organic layers were washed with aq. 1.0 N HCl (600 mL, 4.0 V), followed by 10% brine solution (1.5 L, 10.0 V).
• Step 2 Preparation of N -(4-chloro-1-(2,2-difluoroethyl)-7-nitro-1 H -indazol-3-yl)- N -(4-methoxybenzyl)cyclopropanesulfonamide
• the mixture was poured into ice cold water (3.0 L, 30.0 V) [Note: Slow quenching with vigorous stirring is preferred to avoid clumping as the product precipitates].
• the resulting solids were isolated via filtration and washed with water (300 mL, 3.0 V); then the solids were washed with hexanes (300 mL, 3.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 1-2 h.
• the wet solid was dissolved in ethyl acetate (500 mL, 5.0 V) and charcoal was added (10.0 g). The mixture was heated to 60-70 °C and then stirred for 30-45 minutes at that temperature.
• Step 3 Preparation of N -(7-amino-4-chloro-1-(2,2-difluoroethyl)-1 H -indazol-3-yl)- N -4-methoxybenzyl)cydopropanesulfonamide
• the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by in-process TLC/HPLC), the mixture was diluted with ethyl acetate (1.2 L, 10.0 V) and water (360 mL, 3.0 V). The mixture was stirred for 15 min. The mixture was filtered through Celite and the Celite pad was extracted with ethyl acetate (600 mL, 5.0 V). The bi-phasic filtrate was partitioned, and the organic phase was reserved while the aqueous layer was extracted with ethyl acetate (600 mL, 5.0 V). The combined organic layers were washed with 10% brine solution (1.2 L, 10 V), dried over Na 2 SO 4 .
• Step 1 Preparation of 4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1 H -indazol-3-amine
• the mixture was stirred for 5-10 min, then to the stirred mixture at 10-15 °C was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (60.18 g, 0.26 mol, 1.1 equiv.) at a rate sufficient to maintain the reaction mass below 20 °C (Note: slow addition is preferred for obtaining more favorable regio-selectivity).
• the reaction mass was allowed to slowly warm to room temperature and was then stirred at the same temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched via the addition of ice-cold water (1.5 L, 30.0 V) and the resulting mixture was allowed to warm to room temperature with stirring for 6-8 h.
• the solids were isolated via filtration and were then washed with water (150 mL, 3.0 V). The wet solid was washed with hexanes (250 mL, 5.0 V) and then bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 °C (until the moisture content was below 1.0%).
• the isolated material 4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1 H -indazol-3-amine (45.0 g, 60% yield), was used directly in the next step without further purification.
• Step 2a To a solution of 4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1 H -indazol-3-amine (20.0 g, 0.068 mol, 1.0 equiv.) in DCM (200 mL, 10.0 V) at 0-5 °C. was added triethylamine (29.0 mL, 0.204 mol, 3.0 equiv.), followed by the addition of 4-dimethylaminopyridine (415 mg, 0.03 mol, 0.05 equiv.).
• reaction mass was stirred for 5-10 min., then to the mixture was added methanesulfonyl chloride (13.25 mL, 0.17 mol, 2.5 equiv) at a rate sufficient to maintain the reaction mass below 10 °C.
• the reaction mixture was allowed to warm to room temperature with stirring for 12 h. After completion of the reaction (monitored by TLC), the mixture was diluted with water (200 mL, 10.0 V) and then stirred at room temperature for 15 min. The organic layer was separated, and the aqueous layer was extracted with DCM (200 mL, 10.0 V).
• Step 2b To a stirred solution of N- (4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1 H- indazol-3-yl)- N -(methylsulfonyl)methanesulfonamide (entirety of the material prepared above) in ethanol (200 mL, 10.0 V) at room temperature was added slowly aq. 5% NaOH solution (140 mL, 7.0 V) [Note: Slow addition is preferred via dropping funnel]. The reaction mass was stirred at the same temperature for 2 h. After completion of the reaction [Sample preparation for TLC analysis: An aliquot of the reaction solution ( ⁇ 1.0 ml) was acidified by the addition of aq.
• Step 3 Preparation of N -(4-chloro-7-nitro-1-(2,2,2-trifluoroethyl)-1 H -indazol-3-yl)- N- (4-methoxybenzyl)methanesulfonamide
• the mixture was poured into ice cold water (2.0 L, 40.0 V) [Note: Slow quenching with vigorous stirring is preferred to avoid clumping as the product precipitates].
• the resulting solids were isolated via filtration and washed with water (150 mL, 3.0 V); then the solids were washed with hexanes (150 mL, 3.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 1-2 h.
• the solids were dissolved in ethyl acetate (500 mL, 10.0 V) and to the solution was added charcoal (5.0 g). The mixture was heated to 60-70 °C and then stirred at that temperature for 30-45 min.
• the mixture was filtered while hot (40-50 °C) through a pad of Celite and the Celite pad was extracted with ethyl acetate (250 mL, 5.0 V).
• the combined filtrate was concentrated to dryness under reduced pressure at below 50 °C.
• the solids were combined with ethyl acetate (50 mL, 1.0 V) at room temperature. The resulting suspension was stirred for 30 min.
• the solids were isolated via filtration and then were washed with hexanes (100 mL, 2.0 V). Residual water was removed from the solids by maintaining vacuum filtration for 45-60 min.
• Step 4 Preparation of N -(7-amino-4-chloro-l-(2,2,2-trifluoroethyl)-1 H -indazol-3-yl)- N -(4-methoxybenzyl)methanesulfonamide
• the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by in-process TLC/HPLC), the mixture was diluted with ethyl acetate (1.0 L, 20.0 V) and water (250 mL, 5.0 V). The mixture was stirred for 15 min. The mixture was filtered through a pad of Celite and the Celite pad was extracted with ethyl acetate (250 mL, 5.0 V). The bi-phasic filtrate was partition and the organic layer was reserved while the aqueous layer was extracted with ethyl acetate (500 mL, 10.0 V). The combined organic layers were washed with 10% brine solution (500 mL, 10.0 V), dried over Na 2 SO 4 .
• Example 1 N-((S)-1-(1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide and
• the mixture was then degassed (vacuum evacuation and refill with argon, repeated three times) and then was heated at 100 °C for 16 h.
• the mixture was then cooled to RT, filtered and concentrated in vacuo.
• the residue was taken up in TFA (1 mL) and stirred at room temp for 16 h.
• the mixture was then degassed (vacuum evacuation and refill with argon, repeated three times) and then was heated at 100 °C for 16 h.
• the mixture was then cooled to RT, filtered and concentrated in vacuo.
• the residue was taken up in TFA (1 mL) and stirred at room temp for 16 h.
• the mixture was then degassed (vacuum evacuation and refill with argon, repeated three times) and then was heated at 100 °C for 16 h.
• the mixture was then cooled to RT, filtered and concentrated in vacuo.
• the residue was taken up in TFA (1 mL) and stirred at room temp for 16 h.
• Example 7 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-oxo-4-(6-(trifluoromethyl)pyridin-2-yl)-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide
• the mixture was then degassed (vacuum evacuation and refill with argon, repeated three times) and then was heated at 100 °C for 16 h.
• the mixture was then cooled to RT, filtered and concentrated in vacuo.
• the resulting residue was taken up in TFA (1 mL) and stirred at room temp for 16 h.
• Example 8 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(1-(2,2-difluoropropyl)-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide
• the mixture was then degassed (vacuum evacuation and refill with argon, repeated three times) and then was heated at 100 °C for 16 h.
• the mixture was then cooled to RT, filtered and concentrated in vacuo.
• the residue was taken up in TFA (1 mL) and stirred at room temp for 16 h.
• the reaction mixture was then concentrated and the resulting residue was purified by prep-HPLC to afford the title compound (13 mg, 0.014 mmol, 56.2 % yield).
• the mixture was degassed (brief high vacuum, then refilled with Ar) and then heated at 60 °C for 1h. The mixture was then cooled to room temperature; diluted with water; extracted with ethyl acetate; dried (Na 2 SO 4 ); filtered and the filtrate was concentrated in vacuo.
• the mixture was degassed (brief high vacuum, then refilled with Ar) and then heated at 100 °C for 6 h.
• the mixture was cooled to room temperature; diluted with ethyl acetate; washed with water; dried (Na 2 SO 4 ); and filtered.
• the filtrate was concentrated under reduced pressure and the resulting residue was taken up in DCM (1 mL).
• To the solution was added triflic acid (0.05 mL) and TFA (1 mL). The solution was stirred at rt for 1 h and then concentrated under reduced pressure.
• the residue was dissolved in DMF and then subjected to HPLC purification to afford the indicated product.
• Example 9 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(3-methoxy-3-methylbut-1-yn-1-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 10 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(3-methoxy-3-methylbutyl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 11 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2'-ethoxy-6-oxo-1,6-dihydro-[4,5'-bipyrimidin]-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-ethoxy-5-(tributylstannyl)pyrimidine as the coupling partner.
• Example 12 N-((S)-1-((1'P)-1'-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-ethyl-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 5-ethyl-2-(tributylstannyl)pyrimidine as the coupling partner.
• Example 13 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(5-methoxypyrazin-2-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-methoxy-5-(tributylstannyl)pyrazine as the coupling partner.
• Example 14 N-((S)-1-((1'P)-1'-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-5-ethoxy-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 5-ethoxy-2-(tributylstannyl)pyrimidine as the coupling partner.
• Example 15 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(2-(1,1-difluoroethyl)thiazol-5-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-(1,1-difluoroethyl)-5-(tributylstannyl)thiazole as the coupling partner.
• Example 16 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 4-methyl-2-(tributylstannyl)pyridine as the coupling partner.
• Example 17 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(2-(methylsulfonyl)thiazol-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-(methylsulfonyl)-4-(tributylstannyl)thiazole as the coupling partner.
• Example 18 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-(4-(tributylstannyl)thiazol-2-yl)propan-2-ol as the coupling partner.
• Example 19 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 1-methyl-5-(tributylstannyl)-3-(trifluoromethyl)-1H-pyrazole as the coupling partner.
• Example 20 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-oxo-4-(pyrazin-2-yl)-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-(tributylstannyl)pyrazine as the coupling partner.
• Example 21 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 22 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(6-ethoxypyridin-3-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-ethoxy-5-(tributylstannyl)pyridine as the coupling partner.
• Example 23 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(6-fluoropyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-fluoro-6-(tributylstannyl)pyridine as the coupling partner.
• Example 24 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(5-chloropyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 5-chloro-2-(tributylstannyl)pyridine as the coupling partner.
• Example 25 N-((S)-1-((1P)-1-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(2-(2-hydroxypropan-2-yl)thiazol-5-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 2-(5-(tributylstannyl)thiazol-2-yl)propan-2-ol as the coupling partner.
• Example 26 N-((S)-1-((1'P)-1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6'-oxo-4-(trifluoromethyl)-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 27 N-((S)-1-((1'P)-1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(difluoromethyl)-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 28 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(6-fluoropyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 2-fluoro-6-(tributylstannyl)pyridine as the coupling partner.
• Example 29 N-((S)-1-((1'P)-1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-5-ethoxy-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 30 N-((S)-1-((1'P)-1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-5-fluoro-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 5-fluoro-2-(tributylstannyl)pyrimidine as the coupling partner.
• Example 31 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(5-methoxypyrazin-2-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 2-methoxy-5-(tributylstannyl)pyrazine as the coupling partner.
• Example 32 N-((S)-1-((1'P)-1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(difluoromethyl)-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 33 N-((S)-1-((1'P)-1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-methoxy-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 4-methoxy-2-(tributylstannyl)pyrimidine as the coupling partner.
• Example 34 N-((S)-1-(1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4,6-dimethyl-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 4,6-dimethyl-2-(tributylstannyl)pyrimidine as the coupling partner.
• Example 35 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(5-chloropyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 5-chloro-2-(tributylstannyl)pyridine as the coupling partner.
• Example 36 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 37 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(6-ethoxypyridin-3-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 38 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 5-(tributylstannyl)-2-(trifluoromethyl)pyridine as the coupling partner.
• Example 39 N-((S)-1-((1'P)-1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-5-ethyl-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure A using 5-ethyl-2-(tributylstannyl)pyrimidine as the coupling partner.
• Example 40 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(6-methoxypyrazin-2-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 2-methoxy-6-(tributylstannyl)pyrazine as the coupling partner.
• Example 41 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(3-methoxy-3-methylbut-1-yn-1-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 42 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(1-(2,2-difluoropropyl)-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 43 N-((S)-1-((1'P)-1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-methyl-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 4-methyl-2-(tributylstannyl)pyrimidine as the coupling partner.
• Example 44 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-oxo-4-(6-(trifluoromethyl)pyridin-2-yl)-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 2-(tributylstannyl)-6-(trifluoromethyl)pyridine as the coupling partner.
• Example 45 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(3-methoxy-3-methylbut-1-yn-1-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 46 N-((S)-1-((1'P)-1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6'-oxo-4-(trifluoromethyl)-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 2-(tributylstannyl)-4-(trifluoromethyl)pyrimidine as the coupling partner.
• Example 47 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-4-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 48 N-((S)-1-((1'P)-1'-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 2-(tributylstannyl)pyrimidine as the coupling partner.
• Example 49 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-2'-ethoxy-6-oxo-1,6-dihydro-[4,5'-bipyrimidin]-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 50 N-((S)-1-((1P)-1-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-oxo-4-(pyrazin-2-yl)-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure B using 2-(tributylstannyl)pyrazine as the coupling partner.
• Example 51 N-((S)-1-((1'P)-1'-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-4-(difluoromethyl)-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 52 N-((S)-1-((1'P)-1'-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-6'-oxo-4-(trifluoromethyl)-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure C using 2-(tributylstannyl)-4-(trifluoromethyl)pyrimidine as the coupling partner.
• Example 53 N-((S)-1-((1'P)-1'-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-5-ethyl-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 54 N-((S)-1-((1'P)-1'-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-5-fluoro-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 55 N-((S)-1-((1'P)-1'-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-5-ethoxy-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 56 N-((S)-1-((1'P)-1'-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 57 N-((S)-1-((1'P)-1'-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-4,6-dimethyl-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 58 N-((S)-1-((1'P)-1'-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-4-methyl-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 59 N-((S)-1-((1'P)-1'-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-4-methoxy-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 60 N-((S)-1-((1P)-1-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-6-oxo-4-(6-(trifluoromethyl)pyridin-2-yl)-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 61 N-((S)-1-((1P)-1-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-6-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 62 N-((S)-1-((1P)-1-(4-chloro-1-(2,2-difluoroethyl)-3-(methylsulfonamido)-1H-indazol-7-yl)-6-oxo-4-(pyrazin-2-yl)-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 63 N-((S)-1-((1'P)-1'-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-4-(difluoromethyl)-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 64 N-((S)-1-((1'P)-1'-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6'-oxo-4-(trifluoromethyl)-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• the title compound was prepared according to General Procedure D using 2-(tributylstannyl)-4-(trifluoromethyl)pyrimidine as the coupling partner.
• Example 65 N-((S)-1-((1'P)-1'-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-5-ethyl-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 66 N-((S)-1-((1'P)-1'-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-5-fluoro-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 67 N-((S)-1-((1'P)-1'-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-5-ethoxy-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 68 N-((S)-1-((1'P)-1'-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 69 N-((S)-1-((1'P)-1'-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-4,6-dimethyl-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 70 N-((S)-1-((1'P)-1'-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-4-methyl-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 71 N-((S)-1-((1'P)-1'-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-4-methoxy-6'-oxo-1',6'-dihydro-[2,4'-bipyrimidin]-2'-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example 72 N-((S)-1-((1P)-1-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-oxo-4-(6-(trifluoromethyl)pyridin-2-yl)-1,6-dihydropyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.
• Example IUPAC Name Example 1 N-[(1S)-1-[(1P)-1-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(2S,4R)-9-(difluoromethyl)-5,5-difluoro-7,8-diazatricydo[4.3.0.0 2,4 ]nona-1(6),8-dien-7-yl]acetamide
• Example 2 N-[(1R)-1-[(1P)-1-(4-chloro-3-methanesulfonamido-1-methyl-1H-indazol-7-yl)-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl]-2-(3,5-d
• HIV cell culture assay - MT-2 cells, 293T cells and the proviral DNA clone of NL 4-3 virus were obtained from the NIH AIDS Research and Reference Reagent Program.
• MT-2 cells were propagated in RPMI 1640 media supplemented with 10% heat inactivated fetal bovine serum (FBS), 100 ⁇ g/ml penicillin G and up to 100 units/mL streptomycin.
• FBS heat inactivated fetal bovine serum
• streptomycin 100 ⁇ g/mL
• the 293T cells were propagated in DMEM media supplemented with 10% heat inactivated FBS, 100 ⁇ g/mL penicillin G and 100 ⁇ g/mL streptomycin.
• the recombinant virus was prepared through transfection of the recombinant NL 4-3 proviral clone into 293T cells using Transit-293 Transfection Reagent from Mirus Bio LLC (Madison, WI). Supernatent was harvested after 2-3 days and the amount of virus present was titered in MT-2 cells using luciferase enzyme activity as a marker by measuring luciferase enzyme activity.
• Luciferase was quantitated using the EnduRen Live Cell Substrate from Promega (Madison, WI). Antiviral activities of compounds toward the recombinant virus were quantified by measuring luciferase activity in MT-2 cells infected for 4-5 days with the recombinant virus in the presence of serial dilutions of the compound.
• cytotoxicity and the corresponding CC 50 values were determined using the same protocol as described in the antiviral assay except that uninfected cells were used. Cytotoxicity was assessed on day 4 in uninfected MT2 cells by using a XTT (2,3-bis[2-Methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt)-based colorimetric assay (Sigma-Aldrich, St Louis, Mo).

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